More than 30,000 Americans die by suicide each year. Over 90% of those who complete suicide have a psychiatric illness; 75% of those with a psychiatric illness who complete suicide have a major depression (MDE), schizophrenia (SC) or borderline personality disorder (BPD). We examine the clinical and neurobiological factors related to suicide in high risk samples using a prospective study design. The study is informed by the stress-diathesis model presented in the Overview. No other published study to date has used a multi-variate prospective design focused specifically on suicidal behavior. No other published study to date has used a multi-variate prospective design focused on suicidal behavior. The aims are: 1.) To assess potential clinical predictors of suicide attempts during a two year follow-up in a cohort of 400 patients with major depression (n=200 attempters) and 350 patients with schizophrenia (n=175 attempters). One hundred subjects with MDE will also have BPD; 2.) To study neurobiological and clinical predictors of high versus lower lethality suicide attempts since high lethality attempts can be considered a proxy for complete suicide; 3.) To assess the relationship of serotonergic function (CSF 5-HIAA) to suicide attempt behavior during a two year follow-up of these patients; 4. To assess the relationship of polymorphisms of serotonin-related genes to past and future suicidal behavior and to indices of serotonergic function. Secondary aims are to: 1) examine the role of medication effects on risk for suicidal behavior; 2) examine the interrelationships of SF metabolites, aggression, stress and suicidal behavior. This project relates to Projects #'s 3, 5,6 and 7 of the CCNMD in that it provides neurobiological (CSF metabolite profile and genotyping) assessment, clinical characterization and two year follow up of subjects who participate in other projects (e.g. familial transmission, PET imaging, or statistical methods studies). In addition, this project relies heavily on the cores as follows: 1) The assessment tools of the Clinical Evaluation Core (CEC) are administered; 2) The Clinical Laboratory Core (CLC) analyses neurochemical measures; 3) The Brain Imaging Core (BIC) develops ligands and conducts imaging studies with these well- characterized patients; 4) Finally, all data are entered, managed and analyzed by the Statistics and Computing Core (SCC) of the proposed CCNMD. Using this approach, we can examine risk factors specific to suicide attempters within each of the high-risk groups as well as risk factors consistent across psychiatric diagnostic groups. This will allow testing of the stress-diathesis model for suicidal behavior.